1. Field of the Invention
The present invention relates to a .beta.-oxo-propionitriles active as anti-inflammatory and anti-arthritic agents, to their use in the treatmen of inflammatory or arthritic conditions, and to pharmaceutical compositions containing the novel compounds.
2. Description of Related Art
Benzoylacetonitrile (I) and its monofluoro analogues have been found to be effective inhibitors of adjuvant-induced arthritis in rats (J. Med. Chem., 1979, 22:1385-9). The same article, as well as U.S. Pat. No.4,189,436, also discloses .beta.-oxo-.beta.-thiophenepropionitriles (II) as anti-arthritic agents. ##STR1##
.beta.-Oxopropionitriles having an .alpha.-carbonyl or thiocarbonyl substituent are reported as anti-inflammatory and/or anti-arthritic agents in (a) through (e):
(a) U.S. Pat. No. 4,061,767 and German Offenlegungsschrif No. 2,555,789 disclose, resectively, 2-hydroxyethylidenecyanoacetic acid anilide derivatives of formulas (IIIa) and (IIIb), wherein Ar is inter alia mono-, di-, or tri-substituted phenyl, said substituent may be, for example, halogen, alkyl, alkoxy, or halo-substituted alkyl. ##STR2##
(b) U.S. Pat. Nos. 4,254,047, 4,254,048, 4,254,049, 4,170,656, and 4,173,650 disclose a group of compounds that may be represented by the generic structure (IV) wherein X is oxygen, sulfur, methylene, or a direct bond; Ar is phenyl opt. substituted with one or more of the same of different groups selected from halogen, alkyl, alkoxy, trifluoromethyl, and trichloromethyl. ##STR3##
(c) U.S. Pat. No. 4,197,310 discloses thiophenepropionitriles of formula (V) wherein R is hydrogen, lower alkyl, or halogen. ##STR4##
(d) U.S. Pat. Nos. 4,256,759, 4,644,010 and 4,435,407 disclose .beta.-oxo-.beta.-carbamoylpyrrolepropionitriles encompassed by generic formula (VI) where R.sup.1 is H or alkyl; R.sup.2 and R.sup.3 are independently H or alkyl; and R.sup.4 is phenyl or a heterocyclic radical both of which may be opt. substituted with alkyl, alkoxy, hydroxy, halogen, or trifluoromethyl. ##STR5##
(e) German Offenlegungschrift No. 3,217,446 discloses thiocarbamoyl-thenoylacetonitriles of formula (VII) wherein R.sup.1 is H, halogen, alkyl, or alkoxy; R.sup.2 is C.sub.3-6 cycloalkyl, benzyl, furfuryl, or phenyl opt. substituted with halogen alkyl, alkoxy, alkyllthio, or tribluoromethyl. ##STR6##
(f) British Patent 1,112,210 discloses 2-cyanomalonic acid thioamide derivatives of formula (VIII) wherein R.sup.1 is inter alia alkyl or aralkyl; R.sup.2 is H, alkyl, or aryl; and R.sup.3 is alkyl or aralkyl. ##STR7## These compounds are said to be useful as bactericides, fungicides, and diuretics. No anti-inflammatory or anti-arthritic acivities are disclosed.
(g) The preparation of 3-cyanopentane-2,4-dione from cyanogen and acetylacetone was reported in Berichte, 1898, 31:2944; however, no biological property was disclosed.
Compounds of the present invention may be distinguished over compounds disclosed in items (a)-(g) above by the presence of both the .beta.-cycloalkyl group, and the .beta.-aliphatic substituted carbamoyl group or the .alpha.-alkanoyl group.
A list of additional references disclosing compounds having the .alpha.-carbonyl-.beta.-oxopropionitrile fragment is given below; however, the compounds described therein are not ketonitriles and have not been reported as anti-inflammatory or anti-arthritic agents.
(h) U.S. Paten 3,406,183 discloses 3-N-arylamino-3-mercapo-2-cyano-acrylamides of the formula (IX) wherein R.sup.1 is H and R.sup.2 is alkyl or phenyl; or R.sup.1 and R.sup.2 together represent -(CH.sub.2).sub.4-5 -; and Ar is opt. substituted phenyl. ##STR8## These compounds are alleged to be useful as anhelmintic and antibacterial agents.
(i) Pabst (Arch. Pharm., 1929, 267:325-52) reported the preparation of a series of 2-cyanomalonamic acid esters and amides, for example, (X) and (XI). ##STR9##
(j) U.S. Pat. No. 3,016,295 discloses 2-cyanomalonamic acid ester derivatives having formula (XII) wherein R.sup.2 is alkyl or alkyl-(OCH.sub.2 CH.sub.2 -).sub.1-2 and R.sup.2 is H or alkyl. ##STR10## These compounds are said to be useful in altering growth characteristics of plants.